The AAA+ superfamily of ATPases is found in all kingdoms of living organisms where they participate in diverse cellular processes including membrane fusion, proteolysis and DNA replication. Although the terms AAA+ and AAA are often used loosely and interchangeably, the classical AAA family members are distinguished by their possession of the SRH region in the AAA module. Many AAA+ proteins are involved in similar processes to those of AAA proteins (facilitation of protein folding and unfolding, assembly or disassembly of proteins complexes, protein transport and degradation), but others function in replication, recombination, repair and transcription. For a review see [(PUBMED:11473577)].

The proteins in this superfamily are characterised by the structural conservation of a central ATPase domain of about 250 amino acids called the AAA+ module. Typically, the AAA+ domain can be divided into two structural subdomains, an N-terminal P-loop NTPase alpha-beta-alpha subdomain that is connected to a smaller C-terminal all-alpha subdomain. The alpha-beta-alpha subdomain adopts a Rossman fold and contains several motifs involved in ATP binding and hydrolysis, including classical motifs Walker A and Walker B [(PUBMED:11473577), (PUBMED:18466635)]. The all-alpha subdomain [(PUBMED:9927482)], is much less conserved across AAA+ proteins.

AAA+: A class of chaperone-like ATPases associated with the assembly, operation, and disassembly of protein complexes.

Genome Res. 1999; 9: 27-43

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Using a combination of computer methods for iterative database searches and multiple sequence alignment, we show that protein sequences related to the AAA family of ATPases are far more prevalent than reported previously. Among these are regulatory components of Lon and Clp proteases, proteins involved in DNA replication, recombination, and restriction (including subunits of the origin recognition complex, replication factor C proteins, MCM DNA-licensing factors and the bacterial DnaA, RuvB, and McrB proteins), prokaryotic NtrC-related transcription regulators, the Bacillus sporulation protein SpoVJ, Mg2+, and Co2+ chelatases, the Halobacterium GvpN gas vesicle synthesis protein, dynein motor proteins, TorsinA, and Rubisco activase. Alignment of these sequences, in light of the structures of the clamp loader delta' subunit of Escherichia coli DNA polymerase III and the hexamerization component of N-ethylmaleimide-sensitive fusion protein, provides structural and mechanistic insights into these proteins, collectively designated the AAA+ class. Whole-genome analysis indicates that this class is ancient and has undergone considerable functional divergence prior to the emergence of the major divisions of life. These proteins often perform chaperone-like functions that assist in the assembly, operation, or disassembly of protein complexes. The hexameric architecture often associated with this class can provide a hole through which DNA or RNA can be thread; this may be important for assembly or remodeling of DNA-protein complexes.

Crystal structure of the hexamerization domain of N-ethylmaleimide-sensitive fusion protein.

Cell. 1998; 94: 525-36

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N-ethylmaleimide-sensitive fusion protein (NSF) is a cytosolic ATPase required for many intracellular vesicle fusion reactions. NSF consists of an amino-terminal region that interacts with other components of the vesicle trafficking machinery, followed by two homologous ATP-binding cassettes, designated D1 and D2, that possess essential ATPase and hexamerization activities, respectively. The crystal structure of D2 bound to Mg2+-AMPPNP has been determined at 1.75 A resolution. The structure consists of a nucleotide-binding and a helical domain, and it is unexpectedly similar to the first two domains of the clamp-loading subunit delta' of E. coli DNA polymerase III. The structure suggests several regions responsible for coupling of ATP hydrolysis to structural changes in full-length NSF.

A new family of related ATPases has emerged, characterized by a highly conserved AAA motif. This motif forms a 230-amino-acid domain that contains Walker homology sequences and imparts ATPase activity. Homology between AAA-family members is confined mostly to the AAA domain, although additional homology outside the AAA motif is present among closely related proteins. AAA proteins act in a variety of cellular functions, including cell-cycle regulation, protein degradation, organelle biogenesis and vesicle-mediated protein transport. The AAA domain is required for protein function, but its exact role and the specific activity that it confers on AAA proteins is still unclear. This review describes current understanding of the AAA protein family.

Disease (disease genes where sequence variants are found in this domain)

This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with AAA domain which could be assigned to a KEGG orthologous group, and not all proteins containing AAA domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.